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In the liver, this effect occurs with a concomitant protection against a decrease in GSK3\u03b2\u2010Ser<jats:sup>9<\/jats:sup> phosphorylation. Here, we developed an <jats:italic>in vitro<\/jats:italic> model to investigate this protective effect of VPA and define a molecular mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3\u03b2\u2010Ser<jats:sup>9<\/jats:sup> phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3\u03b2\u2010Ser<jats:sup>9<\/jats:sup> phosphorylation shown <jats:italic>in vivo<\/jats:italic> during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream \u03b2\u2010catenin degradation while increasing histone 2\/3 acetylation. This effect was reproduced by several VPA\u2010related compounds with known PPAR\u03b3 agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPAR\u03b3 blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPAR\u03b3 using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock\u2010like conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Changes in GSK3\u03b2\u2010Ser<jats:sup>9<\/jats:sup> phosphorylation in <jats:italic>in vivo<\/jats:italic> haemorrhagic shock models can be modelled <jats:italic>in vitro<\/jats:italic>, and this has identified a role for PPAR\u03b3 activation in the protective role of VPA.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13320","type":"journal-article","created":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T20:02:29Z","timestamp":1441224149000},"page":"5306-5317","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Valproic acid protects against haemorrhagic shock\u2010induced signalling changes via PPAR\u03b3 activation in an <i>in vitro<\/i> 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